March 6th, 2019
Urinary tract infections (UTI) caused by pathogens such as Escherichia coli, the most prevalent UTI pathogen, have been historically managed with oral agents including the cephalosporins, trimethoprim-sulfamethoxazole (TMP-SMX) and the fluoroquinolones. Not surprisingly, widespread use has resulted in increased resistance over time. When ciprofloxacin was introduced in the mid-1980s resistance among E. coli was largely nonexistent1. Fluoroquinolone-resistant E. coli has progressively increased in the United States from 1.2% in 1998 to 26% in 2017 (SENTRY Surveillance)2. Resistance to the cephalosporins, such as cefuroxime, has increased in parallel with the increasing prevalence of extended spectrum β-lactamase-producing organisms (ESBLs) with 36.8% of UTI E. coli reported as non-susceptible in 2017. Furthermore, resistance to TMP-SMX among E. coli has also increased from 7-9% (1989-1992) to 32% in 2017.
What factors may have contributed to increased resistance to oral therapies among Gram-negative UTI pathogens over time?
Resistance to fluroquinolones: The fluoroquinolones exert their antibacterial effects by inhibiting enzymes that play key roles in DNA replication. The quinolones bind to the complex of each enzyme with DNA and the resulting ternary complex leads to double stranded breaks in DNA blocking the progress of the DNA replication enzyme complex. Fluoroquinolone resistance occurs via several mechanisms including: mutations in the chromosomal genes that encode the subunits of DNA replication enzymes, activation of repair mechanisms that can result in the production of peptides that protect these enzymes from quinolone inhibition, and plasmid mediated resistance mechanisms that can encode antibiotic modifying enzymes or quinolone-efflux resistance mechanisms.
Resistance to cephalosporins: Widespread use of the cephalosporins has resulted in the emergence of organisms that produce extended spectrum β-lactamases (ESBLs). ESBLs have the ability to hydrolyze most penicillin and cephalosporin antibiotics (including those used as oral agents for cUTI) and render them inactive. Importantly, these organisms often exhibit co-resistance to the fluoroquinolones3. A particular driver of the rapid rise of ESBL-based resistance is the increasing prevalence of UTI causing organisms with sequence type ST131, a globally disseminated multidrug resistant clone.5 The ST131 clone of E. coli, that frequently produce the CTX-M-15 ESBL, is predominantly responsible for fluoroquinolone-resistant and cephalosporin-resistant infections that account for millions of antimicrobial-resistant infections globally4.
Resistance to Trimethoprim-sulfamethoxazole: Resistance among organisms such as E. coli is frequently associated with the acquisition of plasmids carrying genes that encode enzymes that confer resistance (e.g., type II dihydrofolate reductase). These plasmids carry resistance genes that are associated with resistance to other antibiotic classes that may also explain the association with fluoroquinolone-resistance. Resistance among E. coli is an important consideration before considering TMP-SMX as empiric therapy.
How often is a pathogen resistant to one oral agent resistant to another?
Resistance to multiple oral agents often travels together in the same pathogen. Recent surveillance data (SENTRY surveillance, JMI Laboratories, North Liberty, IA) on UTI pathogens collected in the United States in 2017 shows that the prevalence of ESBL phenotypes among UTI E. coli was 15.6%. Furthermore, 26% of E. coli isolates from UTIs in the United States are no longer susceptible to levofloxacin. This increase in resistance is now at levels where the fluoroquinolones may no longer be effective as first line agents for Gram-negative UTIs in hospitalized patients. Despite the documented resistance, the fluoroquinolones are still widely used. The widespread and inappropriate use of the fluoroquinolones has resulted in them being described as a “smoking gun” due to their role in promoting resistance development resulting in calls to combat their use as first choice agents for UTIs.6
Contemporary surveillance data on E. coli from UTIs also shows that ESBL phenotypes, fluoroquinolone-resistant and TMP-SMX-resistant isolates exhibit high levels of co-resistance to oral agents routinely used to treat UTIs (Table) that are becoming problematic to treat in the clinic7. The management of UTIs caused by ESBL, fluoroquinolone and TMP-SMX-resistant organisms is therefore increasingly challenging due to the lack of oral treatment options available outside the hospital setting. In contrast, the only agents that retain consistent activity against UTI isolates of E. coli, regardless of resistance, are the intravenous carbapenems such as meropenem and ertapenem.
Why has there been a void in the development of oral options effective against ESBL-producing organisms?
Over the last decade, the pharmaceutical industry has been busy responding to the call for new systemic agents for the treatment of serious infections caused by carbapenem-resistant Enterobacteriaceae (CRE). This has detracted from efforts to develop new oral options for the treatment of UTIs caused by ESBL and fluoroquinolone-resistant Gram-negative pathogens where resistance has been increasing. This void has resulted in an unmet need for new orally bioavailable agents that are effective against contemporary uropathogens with resistance mechanisms that are pervasive today. Although new agents have been approved for cUTIs caused by resistant pathogens (e.g., ceftazidime-avibactam, meropenem-vaborbactam, and plazomicin), none are orally bioavailable. The development of new oral agents is challenging since they must be stable in solid form, dissolve in the gut at the right time and be appropriately transported to the site of infection.
How the unmet need for oral agents effective against resistant UTI pathogens is being addressed.
Oral agents with the spectrum and potency of the intravenous carbapenems would address a substantial unmet need for new options to treat multi-drug-resistant UTI pathogens. The carbapenems are inherently stable to the ESBL and Class C (AmpC) β-lactamase-producing organisms that are common among Gram-negative UTI pathogens. Tebipenem (SPR994) is a new orally bioavailable carbapenem in development that has demonstrated, in pre-clinical and clinical studies, in vitro activity against ESBL (including CTX-M-15 ESBL) and AmpC-β-lactamase-producing organisms as well as FQ-R and TMP-SMX-R isolates of E. coli from UTIs. These data certainly support the continued development of tebipenem as potentially a new option for treating UTIs in an era of ESBLs and co-resistance to many of the currently available agents. The oral prodrug tebipenem pivoxil hydrobromide (SPR994) will be evaluated in a planned Phase 3 clinical trial for efficacy in patients with complicated urinary tract infections or acute pyelonephritis and the results of this trial are eagerly awaited to determine its potential to treat UTIs caused by resistant pathogens.
About the Author(s):
Ian Critchley, Ph.D.
Head of Clinical Microbiology at Spero Therapeutics
1. Karlowsky et al., 2002. Trends in antimicrobial resistance among urinary tract infection isolates of Escherichia coli from female outpatients in the United States. Antimicrobial Agents and Chemotherapy 46: 2540-2545
2. SENTRY Surveillance Program. 2017 JMI Laboratories, North Liberty, IA (www.sentry-mvp.jmilabs/app/sentry-public)
3. Legace-Wiens et al., 2007. ESBL genotypes in fluoroquinolone-resistant and fluoroquinolone-susceptible ESBL-producing Escherichia coli urinary isolates in Manitoba. Canadian Journal of Infectious Disease and Medical Microbiology 18: 133-137
4. Pitout and deVinney. 2017. Escherichia coli ST131: a multidrug-resistant clone primed for global dissemination. F100Research 6: F100 Rev-195
5. Can et al., 2015. Emerging Escherichia coli 025b/ST131 clone predicts treatment failure in urinary tract infections. Clinical Infectious Diseases 60: 523-527
6. Trautner. 2018. Fluoroquinolones for urinary tract infection and within-household spread of resistant Enterobacteriaceae: the smoking gun. Clinical Microbiology and Infection 24: 929-930
7. Talan et al., 2016. Fluoroquinolone-resistant and extended-spectrum β-lactamase-producing Escherichia coli infections in patients with pyelonephritis, United States (1). Emerging Infectious Diseases Sep:22(9). doi/eid2209.160148